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“A FISHING expedition.” These three words, uttered during a grant review, seal the fate of the unfortunate applicant. They infer lack of focus, lack of clear preliminary data or thought, and essentially lack of hypothesis. Many genetic studies suffer from this characterization. But it need not be so. The Human Genome Project, along with similar complete descriptions of the genetic makeup of several subhuman mammalian species, provide an incredible opportunity to probe the genetic determinants of acute and chronic diseases.

The current issue of the Journal contains a review on considerations for designing human genetic studies to examine pain mechanisms. 1 It describes how to fish for genes related to pain. It is not written for geneticists, molecular biologists, or laboratory scientists. For the expert, it provides the necessary formulas and rationale to design trials to study novel genes related to development of chronic pain. For the rest of us, it provides a clear framework in which to phrase questions on the genetic basis of pain. If you have any intention of trying to understand the genetic basis of pain in the next 5 yr, I suggest you carefully read and keep this article.

The nature and nurture discussion states that both inherent and environmental factors determine behavioral biology. There are many reasons to attempt to understand the genetic factors that correlate with the development of chronic neuropathic pain, although they tend to fall into two camps. For one, genetic screening of persons with and without pain may identify novel proteins involved in the process of pathologic pain or targets for novel drug development to treat chronic pain. For another, genetic screening may identify groups or individuals at particular risk for developing chronic pain. The former is the basis of multiple large population studies, mostly done by industry and outside the public domain, in which the plan is to generate intellectual property for sale to develop novel analgesic drugs. No such publicly available screening databases are available, although a few are in the process of being generated, including those of the authors of this report 1 and others. 2,3 The latter are apparently of little interest to industry and have attracted little academic interest.

As anesthesiologists, we are interested both in the treatment of acute and chronic pain and in the prevention of the development of chronic pain. Remarkably, a large proportion of patients with complicated chronic pain problems date the onset of their pain to that of surgery, 4 and to a large extent we can predict which surgical populations are likely to develop chronic pain. 5 As a result, we are in a unique position, as those who treat chronic pain and provide treatment to those undergoing surgery, to affect both. Thus, we are also in a unique position to utilize the information provided in the current report 1 to identify novel targets in the pathophysiology of chronic pain and to identify populations at risk for this devastating problem. We care for these patients in the complete sense of the phrase, and we have available preoperative testing, intraoperative care, and postoperative analgesic methods that could be tailored to individuals, based on the tools provided in this report. 1

Why go on such fishing expeditions? There are two answers to this question, as indicated above. If one wants to drop a line and see what bites, then the key is to use bait that is attractive to anything and everything below. The major focus of the current article, as is especially indicated in its figures, rests on this aspect of global genetic screening. To determine the genetic characteristics associated with chronic pain, the key limitations are the incidence of developing chronic pain in the population and the frequency of the genetic variability (polymorphism) for individual genes. As clearly indicated in the figures, as the number of subjects studied increases linearly, there is an exponential increase in the number of genes that can be screened for a possible association. The “targeted” approach, as suggested in the article, would base the selection of genes in such a scenario on molecules that are considered important in pain processing or in the neuroplasticity of chronic pain. However, as indicated above, a key benefit of this screening approach rests in identifying unsuspected targets and a much larger set of genes than those Belfer et al.
listed. 1 These types of methods have been applied in the laboratory setting to screen for genes that are differentially altered in rat strains that are susceptible or not susceptible to the generation of chronic pain after nerve injury. 6

The problem with this approach is, in a sense, statistical. As discussed in the current article, many associations may be related to environmental influences affecting the development of pain, and these can only be recognized post hoc
. As one screens for many genes, some associations may appear that relate to processes weakly associated with pain, but not causal or closely linked. For example, using a gene microarray to screen for many genes, a recent study demonstrated that peripheral inflammation in the rat results in an increase in expression of the gene for the protein cystatin C in the spinal cord. 7 A follow-up study in humans showed an increase in this protein in lumbar cerebrospinal fluid in women in labor pain, suggesting that this protein might be used as a biomarker for pain. 8 More complete examination, however, showed no relationship between concentration of this substance in cerebrospinal fluid and pain, whether acute or chronic, in humans. 9 Clearly, identification of a potential cause or diagnostic marker for pain using this approach just begins with the genetic screen, with much validation work to follow.

A second reason to fish is exemplified by the fly fisherman, who, as I am told (not being one of them), knows precisely the target, and imagines, or perhaps hallucinates, the location of the fish to be caught. The current article is a similarly effective guide for such fishing. As clearly demonstrated, the number of subjects required to test the relative risk of a specific gene to pain increases dramatically with the extent to which that gene varies in humans and the incidence of chronic pain in the population. Dramatic results have been achieved with this method in other fields, and current work suggests that at least a couple of targets, such as genetic variation in the promoter for tumor necrosis factor α and catecholamine-O-methyl-transferase, are important to postoperative pain and efficacy of analgesia. This approach strives not to identify new targets but rather to demonstrate the relative importance of suspected targets in the pathogenesis of pain.

The beauty of the current article is that it explains how to go fishing regardless of which approach one chooses. Some may find the explanations and equations arcane. No problem. Simply take this article to your local geneticist or molecular pathologist and report your interest in studying the underlying genetic factors, or a specific factor, as a cause of pain. He or she will find the description perfectly sensible in the language of that field of study, and most likely will be delighted to help.

As indicated above, we as anesthesiologists are in a unique position to study the genetics of pain because we treat patients with various genetic backgrounds who are undergoing standardized injuries. A small number of these patients will experience excruciating postoperative pain, and a small number will develop chronic pain following these injuries. Predicting which patients will have either or both of these problems can be determined by one type of fishing, and deciding whether these two experiences—severe postoperative pain and subsequent chronic pain—are related can be determined by the other type of fishing. Thank you to Belfer et al.
for once again providing a guidebook to those who want to better understand pain mechanisms in our patients and how to better treat or prevent pain. Isaac Walton would be proud!